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International STD Research
& Reviews
7(2): 1-15, 2018; Article no.ISRR.42594
ISSN: 2347-5196, NLM ID: 101666147
Prevention and Control of Chagas Disease –
An Overview
A. R. L. Teixeira
1*
, C. Gomes
2
, A. C. Rosa
1
, P. F. Araujo
1
, C. E. Anunciação
2
,
E. Silveira-Lacerda
2
, A. B. Almeida
1
and S. Petrofeza
2
1
Chagas Disease Multidisciplinary Research Laboratory, Faculty of Medicine, University of Brasília,
Brazil.
2
Center for Research and Prevention of Neglected Diseases, Institute of Biology, Federal University of
Goiás, Brazil.
Authors’ contributions
All authors had substantial contribution to the literature review, conception of the work, revised the
work critically for important intellectual content, approved the final version and agree to be
accountable for all aspects.
Article Information
DOI: 10.9734/ISRR/2018/42594
Editor(s):
(1) Anjana Verma, Assistant Professor, Department of Community Medicine, Geetanjali Medical College, Geetanjali Medcity,
India.
Reviewers:
(1)
Alejandro Carabarín-Lima, Benemérita Universidad Autónoma de Puebla, México.
(2)
Natalia Indira Vargas Cuentas, Universidad de Ciencias y Humanidades, Peru.
Complete Peer review History:
http://www.sciencedomain.org/review-history/25651
Received 10
th
May 2018
Accepted 19
th
July 2018
Published 24
th
July 2018
ABSTRACT
Chagas disease is the main cause of heart failure and sudden death in the Western Hemisphere.
The literature of the last decades reported on the changing epidemiological profiles of Chagas
disease, which now threats the human population in the cities. The exodus of the Latin America
people to the Northern Hemisphere explains the growing concern in countries where the
transmission of Trypanosoma cruzi was accidental or transferred from a mother to her offspring.
Herein, we present the evidence of the possible acquisition of the T. cruzi infection by sex. The
staggering demonstration of the transmission of the T. cruzi infections from males and females to
naïve mates by intercourse introduces substantial changes in the surveillance of the Chagas
disease. Notably, the sexual transmission of the T. cruzi introduces changes in the concepts of
medical care, prevention and control; specifically, the risk for the vertical transfer of the parasite-
induced kDNA mutations, underpinning the genetically driven autoimmunity, inheritance, and
pathogenesis associated with multifaceted clinical manifestations of Chagas disease with high
Review Article
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
2
ratios of morbidity and mortality. In this regard, the endemics require much paradigm research with
new approaches and innovation technologies, aiming at its control. For example, the recent
knowledge anticipates useful measures for preventing the potential forthcoming pandemic Chagas
parasites. A long-lasting multicenter research program is needed for creative, drug discovery for
curtailment of Chagas disease. Meanwhile, the prevention shall rely on the education, information,
and communication program for health.
Keywords: Trypanosoma cruzi; sexual transmission; pathogenesis; drug development; prevention;
education.
ACHRONYMS
ATPase : adenyltriphosphatase.
Benznidazole and Nifurtimox : nitroderatives used for the treatment of Chagas disease.
CCD : chronic Chagas disease.
CSB : kinetoplast minicircle constant sequence block.
CYP5128–30 : fenarimol herbicide azole inhibitor of T. cruzi.
EICH : education, information, communication for health.
elF2a : elongation factor 2a.
ELISA : enzyme-linked immunosorbent assay.
IFI : immunofluorescence indirect.
ik2 : eukaryote kinase subunit 2.
EMBL : European molecular biology laboratory.
ERV : endogenous retro virus.
LINE-1 : long interspersed nuclear element-1.
MAL-R : long terminal repeats.
NAT : nucleic acid test.
nDNA
: T, cruzi nuclear DNA.
kDNA : T. cruzi mitochondrion kinetoplast DNA;
PI3K : phosphate inositol 3 kinase.
PCR : polymerase chain reaction.
32
P-dATP : P'-(32)P-labeled; 2'-deoxyadenosine triphosphate.
1. INTRODUCTION
The Kinetoplastid flagellates in the Family
Trypanosomatidae (from greek; trypanon, auger;
soma, body) include Trypanosoma cruzi, the
agent of the American trypanosomiasis [1,2]. The
T. cruzi belongs to the Stercorarian group of
flagellates that accomplishes its life cycle in the
gut of the invertebrate host; the insect sucks in
the blood trypomastigote, which transforms into
epimastigote in the foregut and reverts to
infective metacyclic trypomastigote in the hind
gut. The requirement of an invertebrate host for
completion of the protozoa lifecycle ascribes to
the beginning of the T. cruzi enzootic infection of
mammals that dwell in the American Continent
[3-5]. The enzootics include reservoirs of the
orders Marsupialia, Edentata, Chiroptera,
Carnivora, Artiodactyla, Rodentia and Primates,
upon whom triatomine bugs prey and transmit T.
cruzi [5-7]. The spreading of the T. cruzi
infections requires a broad diversity of triatomine
vectors and mammalian hosts [5-10].
In past decades, the epidemiologic profiles of
American trypanosomiasis and Chagas disease
underwent drastic changes due to the rural
exodus and, therefore, now they become an
emerging urban problem [6-18]. The changes of
the profiles follow pattern of the migration of T.
cruzi-infected people from the South America
continent and their settlement in the Northern
Hemisphere [18].
Herein, we review the literature that describes
the recent change of epidemiologic profiles of the
Chagas disease. The review integrates the
available data and information in men and in
laboratory animals with growing concern about
new technologies for preventing Chagas disease
that threatens the people worldwide [7-19]. With
this respect, this review article presents up-to-
date parasitological, clinic, cell biology,
immunologic, genetic, pathology and the scanty
epidemiologic information for the attention of the
scientific community and for the health
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
3
authorities. The aim of this review is to spurring a
long-lasting program, aiming at a new drug to
treat the carrier and to eradicate the endemic T.
cruzi infections and control of the sexual
transmission of the T. cruzi [18-20]. This review
anticipates that the curtailment of Chagas
disease needs international solidarity and
multicenter research groups to undertake
efficacious, creative, prevention paradigm
achievements. In this regard, a mass-media
Education, Information, and Communication for
Health (EICH) program to prevent Chagas
disease in the forthcoming decades can no
longer be neglected.
2. TRANSMISSION ROUTES
The main public health problem initiated,
possibly, with the accidental triatomine bug-
transmission of the T. cruzi infections to human
[21-23]. However, the route for the bug hindgut’s
trypomastigote entry into the host’s body and
parasitic cell growth, is cumbersome: i) in the
absence of systematic information, it is assumed
that most acute T. cruzi infections stem from
triatomine bug’s bite, supposedly, in hinterland
endemic areas; ii) incomplete knowledge about
the bug’s feces T. cruzi contamination ratios in
countless ecotypes of the America continent [24-
30]; iii) triatomine bug’s night habits, frequency of
accomplishing a full meal and ratios of T. cruzi
contamination, is mostly unknown [27-29]; iv)
quick feeding ability to obtaining a full blood
meal, distension of the abdomen and bug
immediate defecation, remains to be determined
[27-29]; v) triatomine bite site scratch-induced
allergic reactions and vase dilation promotes
bug’s proboscis cannulating and suck-in a full
blood meal, defecation and spread of the
excreta, and the T. cruzi contaminates the
human body [27-29]; nonetheless, in the
absence of an allergic reaction and vase dilation
the prey does not aware about the annoyance
that incites the scratching, which renders much
difficult a full completion of the time consuming
blood meal, defecation and possible
contamination of the host’s body [24-31]; vi) the
frequency of the hypersensitivity lesion at the
port of entry of the parasite in the skin
(Chagoma) or in the eye conjunctiva (Romaña’s
sign) is, possibly, less than circa 1 out of 1000
acute infection [5,6].
The spectrum of drawbacks translates an array
of difficulties towards collecting family information
about bug’s transmitted T. cruzi infections to the
human population. However, the early
recognition of the vector-transmitted T. cruzi
infections posited first in the rank among routes
of the T. cruzi contamination of humans [18,23].
In this regard, further investigation is needed to
determine whether the ratios of T. cruzi-positive
triatomine infestations correlate to the prevalence
of Chagas disease in the cities.
The acquisition of the T. cruzi infections per os is
the most ancient route for the T. cruzi
contaminating the insectivorous mammals’
reservoirs in the wilderness [31-33]. A few
epidemiologic studies refer to the outbreaks of
acute Chagas disease in humans, possibly, by
imprudent ingestion of food contaminated with
the triatomine bug’s feces [2,32,33]. Next, the
acquisition of the T. cruzi infections by blood
transfusion is reported; lately this route of the
infection acquisition is considered, carefully, as
well in several countries of the Northern
Hemisphere [34-36]. Occasionally, the T. cruzi
infections are acquired by accident in the
laboratory and by organ transplantation [36].
The transmission of the T. cruzi from the Chagas
mother to her offspring is an important route of
the infections in humans [36-38]. The congenital
transmission of Chagas disease refers to the in
uterus infection acquisition by the offspring.
However, pregnancy depends upon partnership
and male contribution to the in uterus T. cruzi
infections awaits investigation. In the course of
the pregnancy, the chagasic woman may
undergo early embryo resorption, miscarriage,
death birth, or neonatal death; live births can
either be T. cruzi-infected or infection-free,
healthy baby. Additionally, the infection-free,
healthy progeny can inherit the T. cruzi
mitochondrion minicircle kDNA sequences into
the genome [7].
3. CHAGAS DISEASE
The routes of acquisition of the T. cruzi infections
impose either the silent American
trypanosomiasis or the clinically manifested
Chagas disease. Fair accounts of the prevalence
of those patients are missing and, therefore, the
epidemiologic reports on morbidity and mortality
due to the T. cruzi infections are rather
inconclusive [6]. In the absence of disease
manifestation, chronically infected humans are
intermediate-phase carriers or reservoirs of the
T. cruzi infections [7,37,38]. A majority of
chronically infected individuals remains in the
intermediate phase and their life expectancy is
similar for non-infected individuals [7].
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
4
The field studies show that some chronically
infected individuals develop chronic Chagas
disease (CCD) usually over ~30 years after the
acquisition of the T. cruzi: 94.5% are cases
affected by heart trouble, among which 38.5%
die suddenly, and 56% succumb to heart failure
[6,7]. Sudden deaths are associated with
arrhythmias and heart rate turbulence. In
addition, megaesophagus and megacolon are
revealed in 5.5% of chronically infected people. A
gamut of neurologic syndromes and clinical
dysfunctions are manifestations of Chagas
disease, yet, scarcely studied [7-10]. Moreover,
CCD clinic and pathologic features, which are
indistinguishable from idiopathic inflammatory
dilated cardiomyopathy, have the differential
diagnosis set by the NAT-nDNA test [6,7].
4. DIAGNOSIS
4.1 Trypanosoma cruzi in the Blood
The direct microscopic demonstration of T. cruzi
in the blood is recorded in the early phase of the
infection. Also, the parasite is detected by
concentration methods, such as blood culture
and xenodiagnoses (having a clean bug to feed
upon the patient’s blood). For the epidemiologic
surveys, however, these diagnostics approaches
are out of reach by a majority of the T. cruzi
intermediate phase chronically infected
population, in a lack of late clinical CCD
manifestations.
4.2 Immune Diagnosis
In the absence of a direct demonstration of the T.
cruzi in patient’s blood the diagnosis relies on
searches for the specific antibody. The acutely
infected people are recognized by detecting IgM
antibody class or IgG serum conversion usually
after the second week of infection. Currently,
highly sensitive, but relatively less specific
indirect hemagglutination, enzyme-linked
immunosorbent assay (ELISA), and indirect
immunofluorescence (IFI) tests are routinely
used [41-42]. However, none of these assays
affords complete sensitivity and specificity,
because the host's immune system sees a
plethora of parasitic antigens and clonal selection
of immune responses [6,7,41,42]. A word of
caution is required because a grey zone of
inconclusive assays that yield cross-reactive
antibodies in the serum of patients with
Leishmania sp., Mycobacterium leprae and M.
tuberculosis, Treponema pallidum, or
autoimmune diseases [7,42]. Largely, the
employment of recombinant or synthetic peptide
antigens diminishes the sensitivity of the assays,
and these concerns bear practical consequences
[38,39]. With this respect, caution is required in
order to avoid an accidental T. cruzi-
contaminated blood transfusion. The health
systems should no longer rely solely on testing
the humoral immunity specific T. cruzi antibody
[7,41-47]. Nonetheless, the electrocardiograph
recordings in series of patients from endemic
regions show cases with the positive serum anti-
T. cruzi IgG, increased heart size in the chest X-
rays, and arrhythmias with features of chronic
Chagas disease [48-50].
4.3 Nucleic Acids Test (NAT)
The accuracy of the diagnoses of the T. cruzi
infections to the point-of-care for the assessment
and curtailment of the epidemics, and as well for
the health care delivery to thousands of people
aggravated by the yet incurable Chagas disease,
is fundamental [43-47,51,52]. Therefore, the
diagnosis of the sexually transmitted infection
requires the flagellate protozoa footprint [38-40,
43-47], because the specific IgG antibody is
absent in the immune tolerant progeny of the T.
cruzi-infected parents [38,51-54]. The immune
tolerance showed in the chicken model system
refractory to the T. cruzi infection after the 10
th
day of incubation [38,47,51-54]. The chicks
hatched from T. cruzi-inoculated eggs, which
grow to adult life, do not raise specific antibody
(Y immunoglobulin) after challenge with the
formalin killed parasite [53,54].
The NATs detect T. cruzi nuclear DNA (nDNA)
and its kinetoplast DNA (kDNA) in somatic cells,
and as well in germ cell line of the reproduction
systems immune privilege organs [38,43-47,51-
54]. Moreover, the NAT-nDNA test is an
indispensable condition for the diagnosis of T.
cruzi infection in immune-tolerant patients, in the
absence of the specific antibody. The
development of throughput digital PCR platforms
[47] needed to testing blood donor candidates,
so as deferral of those NAT-nDNA positive blood
donors, and to surveying accurate prevalence
and correct information on the epidemiology of
American trypanosomiasis and Chagas disease.
In so far, the NAT polymerase chain reaction
(PCR) is the basis for research laboratories
diagnosis of the T. cruzi infection and detection
of congenital Chagas disease at birth [38,43-46].
Its employment ensures tidy laboratory practices
to achieve a specific diagnosis of the highly
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
5
repetitive sequences in the flagellate protozoa,
showing homology with human chromosomes;
and throughput platform required for large-scale
epidemiologic surveys. A gamut of nDNA primer
sets is available for in-house PCR diagnosis of
the T. cruzi infections with variable sensitivity and
specificity [38, 44,47]. The Tcz1/2 primers set
that targets a 188-nt telomere DNA repeat in the
T. cruzi genome [48] are used in the family-
based studies [38-51]. The amplicons resolved in
agarose gels and transfer to positively charged
nylon membranes hybridize to the 188-nt α
32
p-
dATP labeled probe, subsequently subjected to
X-Rays film exposure during variable periods.
The positive amplicons are subjected to cloning
and sequencing. The bioinformatics analyses
reveal the 188-nt nDNA footprint in the blood and
in the semen samples. This in-house NAT is the
point-of-care diagnosis of an active T. cruzi
infection [38, 43-46]. Therefore, gold standard
NATs are required to guarantee integrity, purity,
and adequacy of blood bank supply donor
deferral and pathogen inactivation of blood
components. These efforts should be supported
by the health care networks for prevention of an
emerging T. cruzi threat; laboratory procedures
quality control assessment by skilled personnel
are needed to monitor all steps prior to the blood
transfusion and for delivery of the health care.
Additionally, the importance of the NAT tests for
diagnosis of the T. cruzi infection and CCD
cannot be underemphasized because the cross-
section epidemiological surveys based on the IFI
serological assessments of the specific antibody
determine neither the accurate prevalence of the
T. cruzi infections nor the ratios of the parasite
sexual transmission in the human population [38,
41-46].
5. TRANSFER OF KINETOPLAST DNA
(kDNA) FROM AMERICAN
TRYPANOSOMES TO HUMANS
The studies showed transfer of the mitochondrial
DNA (kDNA) minicircles sequences from
T. cruzi to the rabbit’s chromosome [56], and it
was further showed that the Chagas rabbit
progeny retained the protozoan minicircle
sequence mutation into the genome [7, 52-56].
The chicken family studies spurred the human
families’ investigations on the transfer of the
kDNA sequences from Chagas disease parents
to their progeny [54-56]. The founders of study
families showed kDNA minicircle sequences
integrated into the Long Interspersed Nuclear
Element-1 (LINE-1, equivalent to CR1 in the
chicken) of the human genome. In addition, the
kDNA minicircle sequences integrated at various
locations, such as structural, cell growth and
differentiation, immune responses and at
important biochemical pathways checkpoint
genes [52-56].
The development of Chagas heart trouble in the
chronically infected human population is an
ominous sign because the cases succumb to the
autoimmune inflammatory cardiomyopathy either
suddenly or in the range of six months to two
years after the beginning of clinical symptoms
and failure, and, therefore, it is unusual to find
those cases in a cross sectional field study.
Nevertheless, the family study showed the
accumulation of a minimum of 4 to 8 kDNA
mutations into the retrotransposable LINE-1
located at various chromosomes of CCD cases
with clinically manifested heart insufficiency [7,
38, 52-56].
The chagasic parental (F0) vertically transferred
the T. cruzi kDNA minicircle sequences to
the F1 and F2 progeny, which integrated
into the genome [38]. Additionally, the
families study population showed that
somatic cells had the T. cruzi NAT-nDNA positive
tests in family members and that sperm
donors had the active T. cruzi infection.
These findings suggest that intercourse is a
sustainable route for transmission of the T. cruzi
infection [38]. The clinic and epidemiologic
importance of these findings address to the
flagellate life-long infection, the overtime
accumulation of the mitochondrion kDNA
minicircle mutations and Chagas disease
multifaceted manifestations, in which parasite-
induced mutations underpinning the genetically
driven autoimmune pathogenesis, remarkably,
features of host-parasite relationships and
sprouting human disease.
6. SEXUAL TRANSMISSION OF THE
AMERICAN TRYPANOSOMES
In the last decades, the growing number of
Chagas disease in the Northern Hemisphere
inhabitants ever exposed to the insect vectors
suggests the possibility of acquisition of the T.
cruzi infections by the intercourse [7, 38]. In this
regard, the T. cruzi infections encrypted in
immune privilege body niches, in the absence of
inflammatory infiltrates, make the grounds for the
parasitic growth [57-63]
in the reproductive
organs (Fig. 1) and, thus expelling the protozoan
in the semen (Fig. 2) and in the uterine
secretions [38, 57].
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
6
6.1 Family Study
The timely demonstration of the sexually
transmitted T. cruzi in families’ document the
epidemic bursts of the infections in the
population that received health care at the
Center for Chagas Disease Surveillance. Among
individuals in the families, there were cases of
the acute T. cruzi infections showed by direct
demonstration of the blood trypomastigotes.
However, the epidemiologic history of the study
population revealed the absence of the
triatomine-bite transmission of the infections and,
also, the other routes of the infection-acquisitions
were denied.
In the family study, each acute case treated with
the anti-trypanosome nitro derivative
benznidazole (5 mg/kg/day) for 60 days, and all
family members received health assistance for
five years. The individuals in the families yielded
blood samples at 1, 2, and 3 years set points for
serum and DNA collection. Interestingly, the
NAT-nDNA test was consistently positive in 76%
independent assessments of blood samples
collected at three different set points: among
these, 28.4% tested IgG positive. This broad
discrepancy explained by the immune tolerance,
in the absence of the antibody in the majority of
NAT-kDNA positive individuals, since the
sexually transmitted T. cruzi could reach the
early embryo before the development of the
immune system [38,52-57]. Additionally, the
NAT-kDNA test was positive in 92.6% family
members (EMBL HG008116 to HG008708). The
difference between the results obtained by the
NAT-nDNA and the NAT-kDNA approaches
addresses to the mutations resulting from the
integration of the minicircle DNA sequences into
the human genome in the absence of live T. cruzi
infections. (Fig. 3).
In the absence of the T. cruzi antibody, the NAT
analyses of the germ cells collected from
subjects in the family study confirmed the
experimental data [38,52-56] showing that the T.
cruzi infections acquired during early embryo
growth do not bear the specific antibody,
whereas those acquired during fetal development
do not undergo immune-tolerance and, thus
reveal the specific antibody. These analyses
showed the T. cruzi nDNA- and kDNA-specific
bands in the somatic cells of the blood and in the
haploid semen samples examined [38, 57-63]
(Fig. 4). The data that suggest the sexual
transmission of the T. cruzi infections confirmed
by other experiment, in which the injection of 100
µl aliquot of NAT-nDNA positive Chagas patient’s
semen into the peritoneal cavity or its infusion
into the vagina of mice documented the infectivity
of the T. cruzi present in the human ejaculate:
one month thereafter, the growing T. cruzi
amastigote nests appeared in the heart and
skeletal muscles, and in the lumen of the vas
deferens and uterine tube (Fig. 4).
The early epidemiology based serological
surveys conducted in the spare individual
estimate that the prevalence of the T. cruzi
infections averages 7 ± 3 percent of the Latin
America population [6,49]. The family study NAT
assessments revealed much high ratios of the T.
cruzi infections in male and female family’s
founders and progeny mates [38,52-56].
However, the so-called congenital transmission
of the infection means that the woman only bears
for the vertical T. cruzi transmission to her baby.
Certainly, such prejudice definition is in the lack
of scientific understanding, because it omitted
the inevitable roles played by both mates during
the bi-partisan sexual reproduction [38]. With this
respect, further family-based studies at various
ecosystems are required to determine the role
played by the mate’s sexual intercourse in the
transmission of the infectious agent retained in
the immune privilege reproductive organs. The
immune privilege is the absence of destructive
inflammatory reactions to microbes’ antigen
loads in important body structures in the brain,
eyes, and reproductive organs, accomplishing
sensitive functions, reproduction, and the species
survival [64, 65]. The immune privilege
sets free
the T. cruzi growth in the organs of the
reproduction, whereas the immune tolerance [64]
prevents the immune system rejection of the
parasite antigen, because it is recognized as a
component of its own body since early embryo
life.
6.2 Mouse Model System
The pathology searches documented a gamut
of the T. cruzi amastigote nests in the
mouse uterine endometrium, ovary theca
cells, and testicles’ Sertoli cells and in the lumen
of the seminiferous tube, and in the epididymis,
seminal vesicles, prostate, and ureter [57-63].
Actually, the inoculation of the T. cruzi from the
hindgut of a triatomine bug incited the replicative
flagellates’ growth [57] in the recipient mouse
ejaculates (Fig. 2). Furthermore, the T. cruzi
infections were documented upon Chagas
patient’s semen inoculation or infusion in naïve
mice [38].
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
7
Fig. 1. The Trypanosoma cruzi infection in the seminiferous tube of a boy with the acute
Chagas disease. Notice the round amastigote forms in the gonia blasts and clumps of
amastigotes and trypomastigotes in the lumen of the tube (arrows). Bar, 10 µm.
Microphotograph from Doctor Antonio Teixeira’s file, 1970
Fig. 2. The Trypanosoma cruzi parasitic forms in the semen ejaculate of acutely infected mice.
The arrows indicate amastigote (A) within the head of a spermatozoan; free amastigotes (B)
and trypomastigotes (C and D); and the epimastigote forms (E and F) in the semen ejaculates
(arrows). Giemsa stained smears. Bars, 10 µm. Reprinted with permission from the Author and
the Publisher [57]
Fig. 3. The diagnosis of the Trypanosoma cruzi infections made by PCR and Southern
hybridizations. Notice the nuclear DNA (nDNA) bands in 11 Chagas patients with the live
infections, whereas 21 family members showed the mitochondrial DNA (kDNA) bands.
Reprinted with the permission from the Authors and the Publisher [38]
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
8
Fig. 4. The infectivity of the Trypanosoma cruzi from the human semen ejaculates upon aliquot
instills into the peritoneal or into the vagina of naïve mice. Left) the T. cruzi amastigotes clump
in the lumen of the vas deferens. Right) the T. cruzi amastigotes swarm epithelial cells of the
uterine tube (insert, dividing amastigotes). Bars, 10 µm. Reprinted with the permission from
the Authors and the Publisher [38]
Moreover, family studies about the T. cruzi-
infected male and female mice showed the
transmission of the protozoa flagellates to naïve
mates upon intercourse. In those experiments,
each breeding pair placed in one cage inside a
safe box avoided escaping. In experimental
group-A, 10 T. cruzi-infected males mated with
10 naive, control females. In experimental group-
B, 10 T. cruzi-infected females mated with 10
naive, control males [38]. After breeding, groups
A and B mates’ yielded NAT-nDNA bands that is,
the naive mates readily acquired the T. cruzi
after the sexual encounter. The triplicate groups
of independent experiments also showed that
naive female or male mouse that sexually mated
with a T. cruzi-infected male or female acquired
the infection. Those nDNA-positive founders (F0)
generated progeny F1 and F2 that they raised
until six weeks of age. The founders' (F0)
transmitted sexually the infections to F1 progeny
as shown by the nDNA-positive bands. The
breeding of these nDNA-positive mates
generated F2 progeny, which showed the nDNA
bands that indicate the vertically acquired
infections. In these experiments, 58.6% of the
progeny had the NAT-positive nDNA assays, and
22% of the progeny had anti-T. cruzi antibodies.
The results confirmed the absence of the specific
antibody in a majority of F1 and F2 mice (78%)
that bore vertical T. cruzi infections by
intercourse. After that, the tissue sections taken
for microscopic examination showed the T. cruzi
in the reproductive system of those mice [38]. In
summary, those experiments suggest that few
offspring (22%) of chagasic mates had the T.
cruzi-specific antibody, probably, because the
infectious agent reached the fetus with a mature
immune system.
7. DRUG DEVELOPMENT
The strategic for the treatment of Chagas
disease should take into consideration that single
infective T. cruzi initiates a lifelong infection [7].
Regardless of the route of the infection, after
several cycles of division, the T. cruzi ends up in
the reproduction organs immune privilege sites
where it grows [38,64]. The amazing capability of
the T. cruzi to thrive in the immune privilege
mammalian reproductive system, so as to reach
out the route to contaminate the host during
intercourse; the species survival prevail
transmission by sex and warrants the T. cruzi
anthropozoonosis, and, therefore, this new
concept shall guide the preventive medicine and
public health measures for the control of
American trypanosomiasis. This observation
makes the absolute need of the parasite
eradication in order to accomplish cure of
Chagas disease and prevention of the sexually
transmitted infections.
The lead drugs used for the treatment of the T.
cruzi infections are nitro- derivative compounds
nifurtimox [4-(5-nitro-phurylideneamino-)
tetrahydro-4-4-1, 4-thiazine-1-1-dioxide], and
benznidazole [N-benzyl-2-nitro-
imidazoleacetamide) [39-40, 49, 50, 81-84]. Both
drugs achieve elimination of the T. cruzi
infections in vitro but they fail to eradicate the live
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
9
infections in experimental animals and in man
[38,40,66,67], possibly, because after-treatment
non-phagocyte growing nest sustains the
persisting parasite infection. The nitro-derivatives
toxicity includes mutagenic, teratogenic,
carcinogenic and sterilizing activities [68-76],
which relies on the pteridine reductase activity
[85-90] upon the lead and release of high-energy
electron excited intermediates:
-
NO
2
,
-
HO,
1
O
2
,
H
2
O
2
that bind to macromolecules and DNA. The
drug toxicity targets the parasite and the
mammalian host cell [7-79].
8. NEW DRUGS FOR PREVENTING
CHAGAS DISEASE
The Chagas disease reported in five continents
[25-37] has brought much attention from private
and public organizations. In this new look,
searches for safe, efficacious, low-cost drugs to
curtailment of the epidemics needed.
Consistently, the T. cruzi biochemical pathways
checkpoints described herein suggest possible
targets for drug development. The clinical trials
with the 14α-demethylase (CYP51) that
catalyzes the removal of the 14 α-methyl group
from the scaffold revealed that posaconazole and
ravuconazole inhibitors of sterol biosynthesis
undergo treatment failure above that for
benznidazole-treated patients [38,43-50]. The
anti-trypanosome activity of lapachone-based
1,2,3-triazole naphthoquinones derivatives
presented IC50/24 h 80.8 values at 6.8 and 8.2
μM activity which is above that of the anti-T. cruzi
drug benznidazole. The nitro heterocycles
fexinidazole prompted the discovery of the
oxazole AN4169 (SCYX-6759) with anti-T. cruzi
activity in a mouse model. Other leads
derivatives of the herbicide fenarimol, which is an
azole inhibitor of T. cruzi CYP5128–30.
Meanwhile, the nitro derivatives benznidazole
and nifurtimox registered for treatment of Chagas
disease in Latin America [80-82]. In the countries
of the Northern hemisphere the prescription of
these drugs requires license from the health
authorities.
Actually, the sustainable search for compounds
from medicinal plants and drug development to
kill the T. cruzi is needed, because most
antibiotics derived from natural metabolites used
for defense, reproduction, and survival [82-83].
The use of throughput biotechnologies for the
systematic procurement and identification of
active molecules in plants from various
ecosystems, showing enormous biodiversity shall
enhance the chance for obtaining a top lead drug
without toxicity to eradicate the T. cruzi for
prevention and treatment of Chagas disease.
This is a milestone research endeavor.
9. PREVENTING AMERICAN
TRYPANOSOMIASIS AND CHAGAS
DISEASE
Over three decades the World Health Authorities
were at odds with the devastating acquired
immunodeficiency syndrome (AIDS). The
epidemics caused the death of unaccountable
people all over the world, in the lack of the
specific diagnosis, except for the variety of
opportunistic infections in the debilitating immune
tolerant organism. Otherwise, International
Health Authority Organizations consider Chagas
disease minor epidemics that affect the poor
people of Latin America, and the local Health
Institutions claim that the disease is under
control.
Meanwhile, the Chagas disease high morbidity
and mortality ratios are growing burden upon the
health systems worldwide and, therefore, it
should not be neglected anyway (21-37). On the
one hand, the Chagas disease unperceived
epidemics [84-85] require the attention of the
health systems because the potential of
spreading the re-emerging transmission routes,
including the sexually transmitted T. cruzi
infections can no longer be underemphasized.
On the other, the trophic network that enmeshes
the T. cruzi in countless ecotypes in different
ecosystems [4, 8], including the underground
[86], embracing many species of insect vectors,
most of which are not used to domiciliation are
not susceptible to insecticides, and, therefore,
the anthropozoonosis cannot be eliminated by
the vector control strategy. To approach the
magnificent problem the health personnel and
scientists agree that time-consuming,
unprecedentedly sustainable investigation
programs are necessary, in order to create the
knowledge new order to combat this threatening
epidemic, urgently.
9.1 Education Information and
Communication for Health (EICH)
The EICH program, aiming at the control of the
transmission of the T. cruzi infections, is needed.
The population is entitled to know about all
routes of transmission of the T. cruzi infections:
a) sexually transmitted; b) accidental
contamination of health care workers and of
research personnel, and through blood
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
10
transfusion not deferred by the antibody assays;
c) imprudent ingestion of contaminated food; d)
insect-vector transmitted T. cruzi infections,
which are limited to the American Continent. The
a) and b) modes of transmission of the infections
are prone to occur in the five continents. The
basic EICH program to prevent the transmission
of the silent T. cruzi infections shall take some
experience of from AIDS mass-media guidelines,
and the NAT nDNA exam performed early for the
detection of the two weeks period in which the
acute infections run in the absence of the specific
antibodies [38,87,88].
The EICH program should aim at the control of
the epidemics through the involvement of the
people in the community with the knowledge
about the trophic networks that associate the
insect vectors reservoirs with over one
thousands mammal hosts in the indomitable
nature [8]. The information about the several
dozens of the insect species (triatomine bugs)
transmitters of the T. cruzi, thriving in countless
ecotypes, hiding away under tree’s bark, in the
mammals and in the birds’ nests, as well under
the rocks, and in burrows in the undergrounds,
should be promptly delivered to the population [8,
11,17,18]. They should know that a few
triatomine bug species are susceptible to
domiciliation, and those are main targets for
elimination, to assure the family’s protection at
the household.
The EICH guidelines shall sustain the
knowledge, saying that the education tempers
the best health agent in the community.
Additionally, to inform the people in the
community about the genotoxicity of the nitro-
derivative pyrethroid pesticide sprayed in the
house regardless of the inhabiting infants and
adolescents [68,69]. In the case, the health
authorities believe it is necessary to spray the
pyrethroids an informed consent form with the
Family Leader signature is a prerequisite for the
insecticide spraying, in the household free of
infants and adolescents.
A formidable effort is required for developing the
EICH program aiming at the grass roots of the
populations under potential exposures to the T.
cruzi infections. Furthermore, the effective
prevention measures shall sustain the concept
that the EICH efficacy is a lot more protective of
the family in the household than the spray of
pesticides that do not reach most blood fasting
triatomines dispersed in the hideaway
environment. In addition, the citizen under the
benefits of the EICH program shall fight to
eliminate the nasty triatomine bug inside his
house.
The citizens shall be informed about the constant
increasing ratios of the T. cruzi infections in Latin
America and worldwide. The continuous exodus
of the people from Latin America to the Northern
Hemisphere partly explains the many cases of
the Chagas disease in the regions where the
insect-vector does not exist. Meanwhile, the
usefulness of the EICH program at school and at
social organizations, with emphasis on the
sociology, biological and health sciences, and
mass–media communication, shall prevail
worldwide in order to prevent the sexual
transmission of the infections [38,85]. Moreover,
unprecedented drug-discovery program needs
for the parasite eradication and prevention of the
sexually transmitted T. cruzi infections in the
human population.
10. DISCUSSION
The trypanosome survival in invertebrate and in
vertebrate animals include fine strategic
checkpoints such as hiding away underground
and association with countless ecotypes out of
reach of skilled health personnel and
insecticides. The plethora of countless factors,
playing important roles in the multi-factorial chain
of events related to transmission of the T. cruzi
infections requires further studies in the
laboratories and in the field. Meanwhile, the
complexity of the T. cruzi life-cycle does not
sustain the belief that currently used strategies
are good enough for preventing the T. cruzi
infections so as to safeguard the human
population [8]. Such epistemological definition is
essential because not yet defined cumbersome
factors have been brought into play by an
enormously complex chain of events and the T.
cruzi encroaches in major ecosystems. The
discovery of novel preventive and control
strategies should be further investigated by
scholars, before propagating the control of the T.
cruzi infection and Chagas disease is achieved.
Actually, the sexually transmitted T. cruzi
infection undergoes life-long encryption in the
body, and, in the absence of clinic
manifestations, the patients do not seek
preventive medical care. In the absence of a
drug to eradicate the T. cruzi infection, the EICH
program is the corner stone for preventing the
sexual transmission of the American
trypanosomiasis and Chagas disease.
Teixeira et al.; ISRR, 7(2): 1-15, 2018; Article no.ISRR.42594
11
11. CONCLUDING REMARKS
The EICH actions in the American Continent,
concerning the prevention of the triatomines from
close contact with the human population should
be conducted directly in communities,
elementary schools, churches and social clubs,
and reinforced by social marketing and mass
media communications. The population should
be promptly informed about the modes of
transmission of the T. cruzi infections that pose
daily threats to human health. A realistic and
affordable control of the sexually transmitted T.
cruzi infections and the curtailment of Chagas
disease rely on a robust EICH program.
The EICH preventive actions to halt the
American trypanosomyasis and Chagas disease
spread worldwide should be on the time table
because the sexual transmissions of the T. cruzi
infection run simultaneously with the transfer of
the parasitic kDNA to the human genome. This
frailty introduces a significant change in the
concept of public health, and preventive
medicine [7,38,67]. The silent parasite-induced,
genetically driven autoimmunity [38,64-66,67]
associates ubiquitous clinical manifestations with
high ratios of morbidity and mortality several
decades after the infection acquisition, and,
therefore, a conjunction of measures is
necessary to control the Chagas disease and its
potential to become pandemic:
1. Chagas disease is a global problem that
requires international solidarity, consortia,
and exchanges of expertise in order to
provide the means for protection of the
population under risks of acquisition of the T.
cruzi infections.
2. Education, Information, and Communication
mass-media program (EICH) undertaken,
soon is the best, in order to obtain full
compliance from the people’s community,
similar to that employed to control HIV-AIDS
epidemics.
3. Safe new drugs needed to eradicate the
cryptic T. cruzi infections: i) to treat all the T.
cruzi-infected people, so as to prevent the
sexual and the accidental modes of
transmission of the infections. ii) To arrest
the cardiomyopathy: pre-empt the severe
Chagas heart disease case, before the killing
of sick bone marrow progenitors of the
effector immune lymphocytes before healthy
bone marrow transplantation [64,65].
4. Development of throughput digital PCR
platforms for assessing the population under
risk of acquisition of the T. cruzi infections,
so as deferral of NAT-nDNA positive blood
donors.
5. The health personnel should share
responsibility with the community leaders
about the target-directed limited spraying of
the pyrethroid insecticide in the triatomine
bugs infested households.
ACKNOWLEDGEMENTS
This work was funded by the USA NIH grant R03
1164, and by the Brazilian Government
PRONEX/FAPDF/ MCT/ CNPq/CAPES grant
193.000.589/2009. The funders had no role in
study design, data collection and interpretation or
decision to submit the work for publication.
CONSENT
It is not applicable.
ETHICAL APPROVAL
It is not applicable.
COMPETING INTERESTS
The authors have declared no conflict of interest
exists.
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